Epidemiological studies have confirmed that inorganic arsenic is a human carcinogen. It is clear that the complex biotransformation pathways of arsenic undergoes produces several chemical forms of arsenic that vary greatly in their toxicological potency. Thus, it is reasonable to expect that human biotransformation of arsenic is key to its toxic effects. Arsenic biotransformation appears to have a considerable degree of inter-individual variability that has the characteristics of being heritably determined, suggested by a number of studies, including reports of familial aggregation of urinary arsenic metabolite levels. Thus, understanding the metabolism of arsenic is a prerequisite to understanding its toxicological effects in humans. This project will fully characterize the genetic variability of all known genes involved in arsenic biotransformation in a diverse group of ethnically defined, globally collected human samples of arsenic-exposed individuals. Within these populations we will conduct what we believe to be the largest genetic association study to date, with the aim of relating individual variation in arsenic metabolism, measured in two complementary ways-enzymatic activity and urinary metabolite levels, to variations in the DNA sequence of candidate genes involved in arsenic metabolism, including GSTO1-1, PNP, and CYT19. Subsequent Aims will be directed at expressing variant isoforms of candidate gene products and characterizing their biochemical activity to complement the genetic associations with mechanistic information. Finally, this project will continue the group's past success in efforts to identify new arsenic biotransformation pathway members. The successful completion of this work will provide one of the most comprehensive data sets describing the human biotransformation of arsenic, and will be a valuable resource to the scientific community, as well as the general community of stakeholders in the SBRP program.